Pearls and pitfalls in human pharmacological models of migraine: 30 years' experience

Abstract

In vitro studies have contributed to the characterization of receptors in cranial blood vessels and the identification of new possible anti-migraine agents. In vivo animal models enable the study of vascular responses, neurogenic inflammation, peptide release and genetic predisposition and thus have provided leads in the search for migraine mechanisms. All animal-based results must, however, be validated in human studies because so far no animal models can predict the efficacy of new therapies for migraine. Given the nature of migraine attacks, fully reversible and treatable, the headache- or migraine-provoking property of naturally occurring signaling molecules can be tested in a human model. If such an endogenous substance can provoke migraine in human patients, then it is likely, although not certain, that blocking its effect will be effective in the treatment of acute migraine attacks. To this end, a human in vivo model of experimental headache and migraine in humans has been developed. Human models of migraine offer unique possibilities to study mechanisms responsible for migraine and to explore the mechanisms of action of existing and future anti-migraine drugs. The human model has played an important role in translational migraine research leading to the identification of three new principally different targets in the treatment of acute migraine attacks and has been used to examine other endogenous signaling molecules as well as genetic susceptibility factors. New additions to the model, such as advanced neuroimaging, may lead to a better understanding of the complex events that constitute a migraine attack, and better and more targeted ways of intervention.

A review of the neuro- and systemic inflammatory responses in post concussion symptoms: Introduction of the “post-inflammatory brain syndrome” PIBS

“…Inflammation, in particular TNF-a mediated by COX produced prostaglandins, appears to play a major role in the sensitisation of meningeal nociceptors, a key component of the development of migraines (Levy, 2012). IV administration of prostaglandins to both migraine patients and healthy controls was able to produce migraine like attacks, including headache (Ashina et al, 2013). Several cytokines including Il1a and Il-1b, TNF-a and Il-10 are elevated in migraine patients, and prostaglandins are elevated in saliva during attacks (Durham and Papapetropoulos, 2013).…”

Meta-analysis of 375,000 individuals identifies 38 susceptibility loci for migraine

“…Another suggested hypothesis relates to oxidative stress and nitric oxide (NO) signaling. Nitroglycerine and sodium nitroprusside, two pro-drugs delivering NO to tissues can both induce headache in normal patients and migraine in migraine patients 77,78 . Animal experiments have shown relations to superoxide and oxidative stress 79 .…”

Newer Research and its Significance

“…Pharmacological models of migraine have been developed in which these substances were infused intravenously in humans to determine if headaches or migraines were triggered. 60 These studies, as well as others linking these substances to migraine pathophysiology, will be discussed below.…”